The metabolic syndrome is manifested by obesity, insulin resistance, dyslipidaemia and hypertension. Today, the four manifestations are treated by selective treatment paradigmes.
Calcitonin gene-related peptide (hereinafter designated CGRP) is a peptide which, in several species, exists in two forms, designated CGRP-alpha and CGRP-beta (or CGRP-I and CGRP-II, respectively). CGRP peptides are highly conserved within species. For example, the amino acid sequences of human and rat CGRP peptides are mentioned in table 1 in Peptides 20 (1999), 275-84. CGRP is released from, e.g., sensory, motor and enteric nerves.
From the literature it is evident that CGRP triggers various pharmacological effects, e.g.: 1) vasodilation, 2) muscle and liver AMP kinase (AMPK) activation and lipolysis and/or fat oxidation, 3) reduction in food intake, 4) inhibition of gastric emptying and modification of gut function and 5) increasing glycolysis and inhibition of glycogen synthesis. The net physiological significance of the referred effects is not completely understood and no results of chronic CGRP exposure exists (e.g. fasting insulin, HbA1C and sustained vasodilation). Whereas AMPK activation, fat oxidation and reduced food intake may be beneficial in metabolic diseases, glycolysis and inhibition of glycogen synthesis has been suggested to mediate insulin resistance.
Native CGRP has a half life of less than 30 minutes and a short duration of pharmacological actions after CGRP infusions is evident. Due to vasodilatory effects of administered CGRP, in vivo pharmacological studies of native CGRP are contaminated with effects secondary to vasodilation and to compensatory vasoconstrictive actions. Thus, the vasodilatory action is the dose limiting action of CGRP which prevents the complete understanding of the actions relevant to metabolic syndrome. Thus, the pharmacological usefulness of CGRP requires the generation of CGRP analogues with prolonged action and some effects may even only be obtained with prolonged analogues.
Claim 1 in US 2003/0204063 relates to a peptide substituted by 1-5 conformationally rigid moieties selected among six general groups of groups with many possible substituents. In claim 2 therein, 55 peptides are exemplified, for example, CGRP. None of the working examples deals with modified CGRP. According to claim 25 therein, modified CGRP has at least one conformational rigid moiety.